A Role for Endocannabinoids in the Control of Dietary Fat Intake

内源性大麻素在控制膳食脂肪摄入中的作用

• 批准号: 9111460
• 负责人: Nicholas Vincent DiPatrizio
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111460
• 关键词: Address; Adverse effects; Anabolism; Animals; Anti-Obesity Agents; Attention; Automobile Driving; Binge Eating; Biochemical; Biological; Biology; Brain; Brain Stem; Calories; Cannabis; Carbohydrates; Cardiovascular Diseases; Cells; Cephalic; Data; Detection; Development; Diabetes Mellitus; Dietary Fats; Drug Targeting; Eating; Endocannabinoids; Environment; Enzymes; Evaluation; Event; Exposure to; Fatty Acids; Fatty acid glycerol esters; Feedback; Feeding behaviors; Food; Genes; Genetic; Goals; Habitats; Health; Hormones; Human; Intake; Intervention; Intestines; Laboratories; Lead; Lipid Binding; Lipids; Mammals; Mediating; Metabolic; Metabolism; Methodology; Modification; Molecular; Nature; Neural Pathways; Neurobiology; Obesity; Operative Surgical Procedures; Oral; Oral cavity; Pharmaceutical Preparations; Phase; Physiological; Positioning Attribute; Property; Proteins; Rattus; Research; Rewards; Role; Satiation; Sensory; Signal Transduction; Small Intestines; Societies; Taste Perception; Testing; Transcript; Work; abstracting; base; drug of abuse; endogenous cannabinoid system; innovation; insight; neuromechanism; novel; novel therapeutics; obesity treatment; preference; programs; receptor; reinforcer; sham feeding; therapeutic development; tool

Project Summary/Abstract. Mammals have an adaptive advantage in seeking palatable fat-rich foods, which are nutritionally essential but scarce in most natural habitats. In modern societies, where fatty foods are readily available and the energy necessary to find them is minimal, this innate drive can become maladaptive and is considered a primary contributing factor for obesity, cardiovascular disease, and diabetes. Despite its theoretical and practical significance, the neural mechanisms controlling fat preference and compulsive eating are largely unknown. The endocannabinoid (eCB) system, in particular, has gained attention for its key roles in the acquisition and sensory evaluation of natural (e.g., food) and non-natural (e.g., drugs of abuse) reinforcers. The eCBs are endogenous lipids that bind to and activate the same receptors as ∆9-THC, the psychoactive component in cannabis. Recent data from our laboratory indicate that oral exposure to dietary fat stimulates eCB mobilization in the rat small intestine, and localized blockade of this signaling event suppresses fat sham feeding. These results suggest that the intestinal eCB system exerts a powerful regulatory control over fat intake, and provide novel insights into physiological mechanisms that govern preference for fats, which are posited to possess addictive-like properties. The long-term goal of this research program is to utilize state-of- the-art experimental tools to probe the interface of food intake and reward, and thus, elucidate the biological substrates of fat preference and compulsive eating. The central hypothesis of this proposal is that the mobilization of eCBs in the small intestine, elicited by orosensory stimulation by fat-rich foods, contributes to the physiological control of fat intake and the pathophysiological state of obesity. We have three specific aims and unique approaches pertinent to a test of this hypothesis: (i) to identify lipid classes that stimulate intestinal eCB mobilization and promote dietary fat intake by utilizing a combination of surgical, biochemical, and pharmacological tools to identify select lipid classes responsible for driving intestinal eCB signaling and its role in fat preference; (ii) to define changes in intestinal eCB-metabolizing enzymes involved in cephalic-phase fat intake by characterizing modifications to intestinal gene transcripts and proteins involved in eCB metabolism; (iii) to identify oral fatty-acid receptors and neural pathways that maintain intestinal eCB mobilization and fat intake by investigating the ability for fat sham feeding to enhance intestinal eCB signaling in animals that lack the putative fat receptors, and identify the neural pathways that normally transmit this information to the gut. Collectively, the proposed plan will identify physiological mechanisms that control the positive feedback obtained from a fatty meal based on its orosensory properties. Furthermore, the proposal is highly novel because it focuses on an eCB signal in the gut, discovered in our preliminary work, that drives fat intake. Thus, these studies will provide support for the development of anti-obesity drugs that target the eCB system in the periphery, without disrupting central mechanisms that may lead to psychiatric side effects.

项目摘要/摘要。 在现代社会中，在大多数自然栖息地中都是营养的，那里很容易 可用，找到它们的能量很小，这种先天驱动器可能会变坏，并且是IS是IS是IS是IS是IS IS IS IS IS IS IS IS IS IS IS IS IS。 尽管有肥胖，心血管疾病和糖尿病的主要因素 理论和实践意义 尤其是内源性大麻素（ECB）系统，已引起关注 自然（例如食物）和非天然（例如滥用药物）增强剂的自然（例如食物）的获取和感觉评估。 ECB是内源性脂质，与∆9-thc（精神活性）结合并激活相同的受体 大麻的组成部分。 大鼠小肠中的欧洲央行动员，以及对此信号事件的局部封锁事件脂肪假 这些结果表明，肠道欧洲央行系统对 摄入量并提供对控制对脂肪偏爱的生理机制的新见解， 认为具有成瘾性的特性。 探测食物摄入和奖励的界面的艺术实验工具，从而阐明了生物学 脂肪偏爱和强迫性饮食的基础。 小肠中ECB的动员，通过脂肪丰富的食物引起的口感刺激，有助于 脂肪摄入的生理控制和肥胖的病理生理状态。 以及与该假设的检验有关的独特方法：（i）识别刺激肠道的脂质类 欧洲央行动员并通过使用手术，生化和 识别负责驱动肠欧洲央行信号的选择的精选脂质类的药理工具，并且是角色 在脂肪偏爱中； 通过表征对参与欧洲央行代谢的肠道基因转录本和蛋白质的修饰来摄入量； （iii）鉴定静态肠道欧洲央行动员和脂肪的口服脂肪酸受体和神经途径 通过研究脂肪假喂养的能力来增强缺乏动物的肠道欧洲央行信号传导的摄入量 假定的脂肪受体，并确定正常的神经途径将该信息传递给肠道。 总体而言，支撑计划将确定控制积极反馈的生理学机制 从脂肪粉中获得的IS IS感力特性。 因为它专注于肠道中的欧洲央行信号，因此在我们的预序中发现了脂肪的摄入量 这些研究将为抗焦点药物的发展提供支持药物目标目标目标欧洲央行系统的支持 外围，没有可能导致精神病副作用的不chan机制。